Structure of the Catalytic Domain of Avian Sarcoma Virus Integrase with a Bound HIV-1 Integrase-Targeted Inhibitor

The x-ray structures of an inhibitor complex of the catalytic core domain of avian sarcoma virus integrase (ASV IN) were solved at 1.9- to 2.0- angstrom resolution at two pH values, with and without Mn2+cations. This inhibitor (Y-3), originally identified in a screen for inhibitors of the catalytic...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-04, Vol.95 (9), p.4831-4836
Main Authors: Lubkowski, Jacek, Yang, Fan, Alexandratos, Jerry, Wlodawer, Alexander, Zhao, He, Burke, Terrence R., Neamati, Nouri, Pommier, Yves, Merkel, George, Skalka, Anna Marie
Format: Article
Language:English
Subjects:
Active sites
AIDS/HIV
Atomic interactions
Atoms
Avian Sarcoma Viruses - enzymology
Binding Sites
Biological Sciences
Biology
Catalysts
Crystallography, X-Ray
Crystals
Enzymes
HIV
HIV 1
HIV Integrase Inhibitors - chemistry
Human immunodeficiency virus
Hydrogen-Ion Concentration
Integrases - ultrastructure
Manganese
Models, Molecular
Molecular interactions
Molecular Sequence Data
Molecules
Naphthalenesulfonates - chemistry
Protein Structure, Tertiary
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Summary:The x-ray structures of an inhibitor complex of the catalytic core domain of avian sarcoma virus integrase (ASV IN) were solved at 1.9- to 2.0- angstrom resolution at two pH values, with and without Mn2+cations. This inhibitor (Y-3), originally identified in a screen for inhibitors of the catalytic activity of HIV type 1 integrase (HIV-1 IN), was found in the present study to be active against ASV IN as well as HIV-1 IN. The Y-3 molecule is located in close proximity to the enzyme active site, interacts with the flexible loop, alters loop conformation, and affects the conformations of active site residues. As crystallized, a Y-3 molecule stacks against its symmetry-related mate. Preincubation of IN with metal cations does not prevent inhibition, and Y-3 binding does not prevent binding of divalent cations to IN. Three compounds chemically related to Y-3 also were investigated, but no binding was observed in the crystals. Our results identify the structural elements of the inhibitor that likely determine its binding properties.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.9.4831